Typical and atypical antipsychotics are the primary drugs used to treat schizophrenia. Although both groups show similar efficacy against psychosis (e.g., delusions, hallucinations), it is unclear whether atypicals as a class have intrinsic and superior benefits over typicals on symptoms related to motivation, emotion and cognition, independent of their favorable motor side effects. The PI's long-term goal is to understand the neurobiological and behavioral mechanisms of action of antipsychotic drugs. The objective of this R21 application is to use a preclinical approach to identify the extent to which two first-line atypicals (risperidone and olanzapine) exhibit an anxiolytic effect on behavioral and physiological measures of fear and anxiety, as part of broad efforts to delineate the critical differences between typical and atypical antipsychotics on non-psychotic symptoms. The project hypothesis is that risperidone and olanzapine have an intrinsic anxiolytic property in preventing the development of new fearful reactions and in extinguishing existing ones. A conditioned avoidance response model will be innovatively used to test this hypothesis. This model not only has high predictive validity for anti-"psychotic" efficacy, but also encompasses multiple measurable and non- motoric responses reflecting elements of fear and anxiety (e.g., body temperature, defecation, urination, ultrasonic vocalization), which enable evaluation of the anxiolytic properties of various antipsychotics, while carefully matching their anti-"psychotic" efficacy and teasing out any possible influence from their effects on learning or motor functions. Its reliability and sensitivity will be further validated against the elevated plus maze (the gold standard of animal model of anxiety). Aim 1 is to identify behavioral effects of repeated haloperidol (typical), risperidone, olanzapine (atypical), chlordiazepoxide (anxiolytic), citalopram (antidepressant with anxiolytic property) treatment on the acquisition of various conditioned fear responses and conditioned avoidance responding in this model. Aim 2 will explore their effects on the extinction of these responses. Aim 3 will validate this novel approach by examining the behavioral effects of repeated antipsychotic treatment on various measures of anxiety in the elevated plus maze, one of most widely used animal models of anxiety. This project is innovative in that a single behavioral paradigm will be used to concurrently identify antipsychotic and anxiolytic efficacies of the drugs, while other confounding factors (e.g., drug effects on learning, memory or motor functions) are being carefully controlled. The reliability of the data is expected to be high because a wide range of doses of typical and atypical drugs will be compared directly with anxiolytic drugs and multiple measures of fear/anxiety will be collected. Furthermore, a repeated drug treatment regimen instead of an acute one will provide better modeling of the clinical treatment condition. This project is designed to reveal the extent to which the two most widely prescribed atypical antipsychotic drugs, risperidone and olanzapine, alleviate anxiety or fear at different stages of development. Such findings are expected to have a positive impact on the development and evaluation of psychotropic drugs and on the treatment of patients with schizophrenia.